What does phospholipase A2 act on to start the arachidonic acid cascade?
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Clinical Pharmacology · Anti-Inflammatory and Immunosuppressive Medications
NSAIDs
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In 30 seconds
NSAIDs (ibuprofen, naproxen, indomethacin, celecoxib, and relatives) block cyclooxygenase enzymes to shut down prostaglandin production, reducing inflammation, fever, and pain. In rheumatic disease they are frontline symptom control for osteoarthritis and spondyloarthropathies, and useful adjuncts in rheumatoid arthritis, gout flares, and pericarditis. Their critical limitation: they calm inflammation's signals without slowing the immune destruction driving diseases like rheumatoid arthritis, so they never substitute for disease-modifying therapy. Their toxicity — GI, renal, and cardiovascular — tracks directly from blocking the same enzymes that protect the stomach lining and kidneys.
The college version
The arachidonic acid cascade
When cell membranes are disturbed by injury, infection, or immune activity, phospholipase A2 clips arachidonic acid out of membrane phospholipids. Arachidonic acid is the shared raw material for two branches. Lipoxygenase converts it into leukotrienes, mediators central to bronchoconstriction and allergic inflammation. Cyclooxygenase (COX) converts it into prostaglandins and thromboxane, mediators of pain, fever, and vascular tone. Corticosteroids act upstream of both branches by inhibiting phospholipase A2 itself, suppressing leukotrienes and prostaglandins together — this is why steroids have a broader anti-inflammatory effect, and broader toxicity, than NSAIDs, which act only downstream on the COX branch.
What prostaglandins do
COX-derived prostaglandins cause local vasodilation and increased vascular permeability, producing the redness, warmth, and swelling of inflammation. They sensitize peripheral nerve endings to painful stimuli, lowering the pain threshold and amplifying signals from mediators like bradykinin. In the hypothalamus, prostaglandin E2 raises the body's temperature set point, producing fever. Certain prostaglandins also protect gastric mucosa via mucus and bicarbonate secretion and maintain mucosal and renal blood flow — the basis for much of NSAID toxicity.
COX-1 versus COX-2
COX-1 is constitutively expressed and produces "housekeeping" prostaglandins protecting the stomach lining, supporting platelet thromboxane (clot formation), and maintaining renal perfusion. COX-2 is largely induced at sites of inflammation, producing the prostaglandins responsible for pain, swelling, and fever, though it has some constitutive roles too, including in the kidney and vascular endothelium. Nonselective NSAIDs (ibuprofen, naproxen, indomethacin, diclofenac) inhibit both isoforms — effective against inflammation, but at the cost of COX-1's protective gastric and platelet effects. Celecoxib selectively inhibits COX-2, preserving anti-inflammatory efficacy while reducing GI ulceration risk, making it preferred for patients with ulcer history or high GI-bleed risk. The trade-off: COX-2 inhibition removes vascular-protective prostacyclin without touching platelet thromboxane, tipping the balance toward clot formation and raising cardiovascular risk, particularly in patients with existing cardiovascular disease.
Clinical uses in inflammatory and rheumatic disease
NSAIDs are a mainstay for osteoarthritis, reducing joint pain and stiffness from mechanical and low-grade inflammatory damage. They provide meaningful symptom relief in rheumatoid arthritis, easing pain and morning stiffness, but do not alter underlying autoimmune joint destruction. They are notably effective in spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis), often producing dramatic improvement in axial stiffness, sometimes used near-continuously. They are also standard for acute gout flares, rapidly reducing crystal-induced synovitis, and for pericarditis, easing inflammation of the pericardial sac and associated chest pain.
The disease-modifying limitation
The central pharmacologic lesson: NSAIDs treat the downstream chemical signals of inflammation but do nothing to the upstream immune process generating them. In rheumatoid arthritis, that upstream process is ongoing synovial immune activation and joint erosion. Relying on NSAIDs alone lets structural damage progress silently while symptoms feel controlled — precisely why disease-modifying antirheumatic drugs (DMARDs) are started early and aggressively, with NSAIDs used only as adjunct symptom relief.
Adverse effects
GI ulceration and bleeding are the signature toxicity, from loss of protective COX-1-derived prostaglandins; chronic NSAID users, especially older adults or those with prior ulcers, are frequently co-prescribed a proton pump inhibitor to reduce this risk. Renal effects include reduced glomerular filtration from loss of prostaglandin-mediated afferent arteriolar dilation, most significant in volume-depleted or already compromised kidneys. Sodium and water retention can cause edema and raise blood pressure, complicating hypertension management. Cardiovascular risk (myocardial infarction, stroke) is elevated with COX-2-selective agents and some nonselective agents at higher exposures. Finally, aspirin-exacerbated respiratory disease is a triad of asthma, nasal polyps, and severe bronchospasm triggered by aspirin or other NSAIDs, thought to result from COX inhibition shunting arachidonic acid toward the lipoxygenase pathway and excess leukotriene production; these patients should avoid NSAIDs broadly.
Eli explains
The same idea, in plain words
Explain it like I’m 10
Picture a factory that makes two kinds of alarm chemicals when your body gets hurt. One kind causes swelling, redness, pain-sensitivity, and fever — like a fire alarm in a hurt joint. The other, in a different part of the same factory, keeps your stomach lining safe and your kidneys running well. NSAIDs are a switch that turns down the fire-alarm machine, but the switch is wired close enough to the stomach-and-kidney machine that it gets turned down too — why NSAIDs can upset stomachs and stress kidneys. Steroids pull the master power line further upstream, shutting down even more alarm chemicals — more powerful, but with more side effects. And here's the catch for rheumatoid arthritis: NSAIDs only quiet the alarm noise. They don't stop the reason the alarm keeps going off, so doctors add different medicines that calm the misbehaving immune system itself.
Check yourself
2 review questions from the chapter. Try each one, then open the answer.
A patient with long-standing rheumatoid arthritis has managed symptoms with an NSAID alone for two years and now shows new joint erosion on imaging. What pharmacologic explanation accounts for this progression despite symptom control?
Show answer
Structural damage kept progressing because NSAIDs only suppress prostaglandin-driven symptoms like pain and swelling; they do nothing to stop the autoimmune synovial inflammation actually eroding the joint.
The alarm bells were quieted, but the underlying immune attack on joint tissue continued unchecked the whole time — exactly why NSAID-only management is discouraged in rheumatoid arthritis.
A patient with asthma and nasal polyps takes ibuprofen for menstrual cramps and develops acute severe wheezing. What is this reaction called, and what pathway shift is thought to cause it?
Show answer
This is aspirin-exacerbated respiratory disease, thought to occur because blocking COX shunts arachidonic acid toward the lipoxygenase pathway, producing excess leukotrienes that trigger severe bronchoconstriction.
With COX blocked, the raw material has nowhere to go except the other branch, and a surge of leukotrienes is a powerful trigger for airway squeezing in susceptible patients.
Quick check
3 questions here. Answers stay hidden until you check.
Why is celecoxib often chosen for a patient with a history of peptic ulcer disease who needs anti-inflammatory therapy?
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Why do corticosteroids have both a broader anti-inflammatory effect and a broader toxicity profile than NSAIDs?
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